Tukysa (tucatinib)

P3, N=400, Recruiting, Seagen, a wholly owned subsidiary of Pfizer | Trial completion date: Jul 2029 --> Jul 2030 | Trial primary completion date: Apr 2026 --> Dec 2027

Treatment of HER2+ mBC with and without BMs in Saudi Arabia largely aligned with international recommendations identified in our literature analysis, although access to lapatinib, tucatinib and neratinib can be limited and may lead to use of alternative regimens. The tucatinib-combination may be considered the standard of care for adult patients with HER2+ locally advanced or mBC who have received at least two prior anti-HER2+ treatment regimens, including patients with BMs. Ensuring access to innovative HER2+ mBC therapies across Saudi Arabia is crucial to supporting best practice.

Molecular docking identified tucatinib as a brain-penetrant pharmacologic disruptor of FAM3C-SPIN1 interactions, promoting SPIN1 degradation and reducing intracellular proline levels. Thus, cancer stem cells induced a favorable metabolic state through proline synthesis and ROS depletion, revealing potential therapeutic dependencies.

P=N/A, N=300, Recruiting, Fondazione Oncotech

P1/2, N=18, Active, not recruiting, Jonsson Comprehensive Cancer Center | Trial completion date: Apr 2027 --> Apr 2028 | Trial primary completion date: Apr 2026 --> Apr 2027 | Recruiting --> Active, not recruiting

P2/3, N=650, Recruiting, Hoffmann-La Roche | Not yet recruiting --> Recruiting

P1/2, N=129, Not yet recruiting, Medica Scientia Innovation Research S.L.

On the basis of 110 ns MD simulations, it was concluded that trilaciclib, tucatinib and olmutinib can be considered candidate inhibitors for HsFN3K inhibition. These drugs are expected to have favourable in-vitro and in-vivo activity inhibiting HsFN3K on the basis of our results. The online version contains supplementary material available at 10.1007/s40203-026-00635-2.

Strikingly, knock-in mice expressing a patient-derived HER2 variant and mice maternally exposed to Tucatinib, a recently approved anti-HER2 drug, both replicated patient phenotypes: retarded growth and diverse craniofacial abnormalities, including ocular dysgenesis, short jaws, and cleft palate. Collectively, our findings define a developmental disorder that we designate GRACE syndrome (Growth Retardation and Craniofacial Malformations Caused by HER2 Deficiency), establish HER2's essential role in human growth and craniofacial morphogenesis, and reveal that HER2-targeted therapies during pregnancy can induce craniofacial defects and lifelong growth impairment in fetuses. 5.

P2/3, N=107, Not yet recruiting, F. Hoffmann-La Roche AG

In the PATINA trial, the addition of palbociclib to trastuzumab, pertuzumab, and endocrine therapy was associated with a clinically meaningful improvement in progression-free survival in hormone receptor-positive, HER2-positive metastatic breast cancer...More recently, HER2-CLIMB-05 demonstrated that the addition of tucatinib to dual HER2 antibody therapy significantly prolonged progression-free survival, supporting a model of sustained, multi-agent HER2 pathway suppression...Collectively, these advances support a translational framework in which antibody therapy serves as a central component of treatment strategies, with targeted partners selected according to tumor biology and prior therapy. This review summarizes the biological basis, clinical evidence, and future perspectives of antibody-driven maintenance in HER2-positive metastatic breast cancer.

The HER2 inhibitors represent different mechanisms of actions, including trastuzumab, pertuzumab, tucatinib, and lapatinib, all of which are clinically approved, as well as PEPDG278D, a recombinant human protein which was previously shown to induce the degradation of HER2 and epidermal growth factor receptor (EGFR). Despite p95HER2 expression and resistance to current HER2 inhibitors, HER2-positive BC cells and tumors are highly vulnerable to PEPDG278D-induced degradation of HER2 and EGFR. By inducing HER2 degradation, PEPDG278D eliminates p95HER2 in HER2-positive BC cells and tumors.